PROJECT SUMMARY Alzheimer?s disease (AD) is a progressive neurodegenerative disorder that affects more than 5 million people in the United States. The underlying cause of neuronal synaptic loss and neurodegeneration in AD is incompletely understood. Recent studies have directed research efforts towards elucidating the role of microglia and neuroinflammation in the progression of AD. Phosphatidylinositol-3,4,5,-triphosphate 5-phosphatase 1 (INPP5D/SHIP1) is a phosphatase that is a negative regulator of PI3K/Akt signaling, and this enzyme has a known role in suppressing macrophage activation in the peripheral immune system. The expression of SHIP1 is restricted to cells of the hematopoietic lineage, which includes microglia. rs35349669, an INPP5D-associated SNP, has been implicated in an increased risk for late-onset or sporadic Alzheimer?s disease (LOAD) in a large GWAS meta-analysis. Furthermore, the products of the enzymatic activity of SHIP1 have been linked to AD- relevant signaling cascades. The goal of this proposal is to understand the function of SHIP1 in microglia and to investigate whether SHIP1 plays the same immune modulatory role it does in microglia that it does in peripheral macrophages. The studies outlined in Aim 1 will test the hypothesis that SHIP1 is a negative regulator of microglia immune activation by examining both patient-derived induced pluripotent stem cell (iPSC) derived microglia-like cells (iMGLs) as well as microglia in vivo in microglia-specific SHIP1-deficient mouse models. The studies outlined in Aim 2 will work to understand the functional consequence of SHIP1 activity and signaling in the microglia on neurons, specifically through quantification of neuronal synapse numbers by culturing iMGLs with iPSC-derived neurons (iN) in an in vitro co-culture system as well as in microglia-specific SHIP1-deficient AD mouse models. Ultimately, understanding the role that SHIP1 plays in microglia immune activation and activity will allow for a greater understanding of AD pathobiology and to better define the molecular processes underlying innate microglial biology.